1. Field of the Invention
This invention relates to (p-o-sulfamoyl)-N-alkanoyl p-hydroxy phenylamine compounds. More specifically, it relates to non-steroidal compounds useful as steroid sulfatase inhibitors in estrogen dependent illnesses. Methods of employing these compounds for therapeutic and prophylactic treatment are also provided.
2. Background Information
Estrogen levels in breast tumors of post-menopausal women are at least ten times higher than estrogen levels in plasma. [Millington, "Determination of hormonal steroid concentrations in biological extracts by high resolution fragmentography", J. Steroid Biochem., Vol. 6, pp. 239-245 (1975).] The high levels of estrogen in these tumors is due to in situ formation of estrogen, possibly through conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. [Santner et al., "In situ estrogen production via the estrone sulfatase pathway in breast tumors: Relative importance versus the aromatase pathway, J. Clin. Endocrinol Metab., Vol. 59, pp. 29-33 (1984); Santen et al., "Enzymatic control of estrogen production in human breast cancer: Relative significance of aromatase versus sulfatase pathways", Ann. N. Y. Acad. Sci., Vol. 464, pp. 126-137 (1986).] Therefore, inhibitors of estrone sulfatase are potential agents for the treatment of hormone-dependent breast cancer. Most estrone sulfatase inhibitors are estrone derivatives. Reed and his co-workers reported on the sulfatase inhibitory activities of estrone-3-0-methylthiophosphonate, estrone 3-0-alkyl and aryl sulfonates, estrone-3-0 phosphonates and thiophosphonates and estrone sulfamates on MCF-7 cells and in human placental microsomes and breast tumor preparations. [Duncan et al., "Inhibition of estrone sulfatase activity by estrone 3-methylthiophosphonate", Cancer Res., Vol. 53, pp. 298-303 (1993); Howarth et al., "Phosphonates and thiophosphonates as sulfate surrogates: Synthesis of estrone-3-methylthiophosphonate, a potent inhibitor of estrone sulfatase", Bioorg. Med. Chem. Lett., Vol. 3, pp. 313-318 (1993); Howarth et al., "Estrone Sulfamates: Potent inhibitors of estrone sulfatase with therapeutic potential", J. Med. Chem., Vol. 37, pp. 219-221 (1994).] From studying the synthesis and sulfatase binding affinity studies of estrone phosphate, desoxyestrone-3-methylene sulfonate, it was hypothesized that an oxygen atom or at least a sterically or electronically similar link between the steroid ring and the sulfonate moiety is essential for high affinity binding to the sulfatase. [Li et al., "Synthesis and biochemical studies of estrone sulfatase inhibitors", Steroids, Vol. 58, pp. 106-111 (1993); Dibbelt et al., "Inhibition of human placental sterylsulfatase by synthetic analogs of estrone sulfate", J. Steroid Biochem. Molec. Biol., Vol. 50, Nos. 5/6, pp. 261-266 (1994)]. Of all the reported estrone sulfatase inhibitors in the literature, estrone 3-0 sulfamate is the most potent inhibitor. However, in uterine weight gain assay in rats, estrone 3-0 sulfamate and its analogues is estrogenic (unpublished result) and, therefore, is not useful in the treatment of hormone-dependent breast cancer.
Therefore, in spite of the prior art disclosures, there remains a very real and substantial need for a non-steroidal estrone sulfatase inhibitor that is more metabolically stable, more active and more selective than other known sulfatase inhibitors. There is also a need for these non-steroidal estrone sulfatase inhibitors to have antitumor activity or act as synergistic agents with antiestrogen and aromatase inhibitors and for methods of using these compounds.